Statistical Analysis Plan Research Articles

Risk of bias in randomized clinical trials on psychedelic medicine: A systematic review.

The classical psychedelics, psilocybin, peyote, ayahuasca/N,N-dimethyltryptamine, and lysergic acid diethylamide are considered promising new treatments for psychiatric illnesses, such as depression, anxiety, addiction, and obsessive-compulsive disorders. However, their profound and characteristic subjective effects raise concern for distinctive biases in randomized clinical trials. We performed a systematic literature search to identify all clinical trials on classical psychedelics with patient populations to examine descriptive data and determine the risk of bias. Two independent reviewers searched three databases (PubMed, Embase, and APA PsycNet) and extracted information on study design, study population, use of active or inactive placebo, dropouts, evaluation of blinding of intervention, and reporting of expectancy and therapeutic alliance. We included 10 papers reporting on 10 unique trials. The trials generally included populations that were predominantly white and highly educated. The trials had small samples and considerable dropout. Blinding was either unsuccessful or not reported regardless of type of placebo. Few trials published protocols, statistical analysis plans (SAPs), and outcomes relating to psychotherapy fidelity. All trials but one were rated as high risk of bias. Successful blinding of intervention is a significant challenge in this field. To better accommodate this, we suggest that future trials use a parallel-group design and utilize an active placebo on a psychedelic-naïve population. Future trials should publish trial protocol and SAPs, use clinician-rated outcomes accessed by a blinded rater, evaluate blinding of intervention, and consider measuring expectancy and therapeutic fidelity.

Study protocol of the WashT Trial: transfusion with washed versus unwashed red blood cells to reduce morbidity and mortality in infants born less than 28 weeks’ gestation - a multicentre, blinded, parallel group, randomised controlled trial

IntroductionMany extremely preterm newborns develop anaemia requiring a transfusion, with most receiving three to five transfusions during their admission. While transfusions save lives, the potential for transfusion-related adverse outcomes is...

Growth patterns in patients with mucopolysaccharidosis VII

ObjectiveThis study assessed growth patterns in patients with mucopolysaccharidosis (MPS) VII before enzyme replacement therapy. MethodsHeight, weight, and body mass index (BMI) measurements and Z-scores from patients from three clinical studies were compared with those from CDC healthy population growth charts. Relationships with age/sex and history of non-immune hydrops fetalis (NIHF) were assessed by linear regression and ANOVA, respectively. ResultsAmong 20 enrolled patients with MPS VII, height Z-scores were near normal until 1 year of age but declined thereafter, particularly among males. There was no consistent pattern in weight Z-score. BMI Z-scores were above normal and increased slightly with age among males and were slightly below normal among females. Male patients with a history of NIHF had greater declines in height and weight Z-scores over time versus males without history of NIHF. There was no clear effect of NIHF history on height and weight Z-scores in female patients. ConclusionsIn patients with MPS VII, declines in height Z-score began early in life, particularly among males, while changes in BMI varied by sex. Patients with MPS VII and a history of NIHF had greater declines in height Z-score with age than did patients without a history of NIHF.Clinical trial registration: This retrospective analysis included patients enrolled in an open-label phase 2 study (UX003-CL203; ClinicalTrials.gov, NCT02418455), a randomized, placebo-controlled, blind-start phase 3 study (UX003-CL301; ClinicalTrials.gov, NCT02230566), or its open-label, long-term extension (UX003-CL202; ClinicalTrials.gov, NCT02432144). Requests for individual de-identified participant data and the clinical study report from this study are available to researchers providing a methodologically sound proposal that is in accordance with the Ultragenyx data sharing commitment. To gain access, data requestors will need to sign a data access and use agreement. Data will be shared via secured portal. The study protocol and statistical analysis plan for this study are available on the relevant clinical trial registry websites with the tabulated results.

A template for the authoring of statistical analysis plans

A number of principal investigators may have limited access to biostatisticians, a lack of biostatistical training, or no requirement to complete a timely statistical analysis plan (SAP). SAPs completed early will identify design or implementation weak points, improve protocols, remove the temptation for p-hacking, and enable proper peer review by stakeholders considering funding the trial. An SAP completed at the same time as the study protocol might be the only comprehensive method for at once optimizing sample size, identifying bias, and applying rigor to study design. This ordered corpus of SAP sections with detailed definitions and a variety of examples represents an omnibus of best practice methods offered by biostatistical practitioners inside and outside of industry. The article presents a protocol template for clinical research design, enabling statisticians, from beginners to advanced.

Sex and age do not modify the association between glucocorticoids and bone mineral density in patients with rheumatoid arthritis: a cross-sectional study

BackgroundIt is unclear whether sex or age modify the association of glucocorticoid (GC) use with reduced bone mineral density (BMD) in patients with rheumatoid arthritis (RA).MethodsWe studied cross-sectional data of RA patients with current or previous GC treatment in a single center cohort study (Rh-GIOP cohort). Our primary outcome was the minimum T-score (measured by DXA) of either lumbar spine, total femur, or femoral neck. Current GC dose was the main exposure; cumulative GC dose and cumulative duration of GC use were also assessed. Following a predefined statistical analysis plan, linear regression analyses with adjustment for confounders assessed whether the association of GC use with BMD was modified by sex (men versus women) or age (≥ 65 versus < 65 years).ResultsFour hundred eighty-three patients with RA (mean age 64 ± 12 years, 80% women) were included. 33% were not currently taking GCs, 32% were treated with a dose of 5 mg/d prednisone equivalent and 11% with more than 7.5 mg/d. 23% of patients had osteoporosis by DXA (minimum T-score ≤ -2.5). The slope, i.e., the association between changes in minimum T-scores with 1 mg/d change in current GC dose, was similar in men and women (-0.07 and -0.04, respectively; difference -0.03 [-0.11 to 0.04]; p for interaction = 0.41). Slopes were also similar for elderly and non-elderly patients (-0.03 and -0.04, respectively; difference -0.01 [-0.06 to 0.05]; p for interaction = 0.77). Using cumulative dose and duration of use as exposures did not lead to substantial changes of these results.ConclusionsIn our sample, the association of GC use with reduced BMD in RA was not modified by sex or age.

Peer review before trial conduct could increase research value and reduce waste

Traditional peer-review of clinical trials happens too late, after the trials are already done. However, lack of methodological rigor and presence of many biases can be detected and remedied in advance. Here, we examine several options for review and improvement of trials before their conduct: protocol review by peers, sponsors, regulatory authorities, and institutional ethical committees; registration in registry sites; deposition of protocol and/or the statistical analysis plan in a public repository; peer-review and publication of the protocol and/or the statistical analysis plan in a journal; and Registered Reports. Some practices are considered standard (e.g. registration in trial registry), while others are still uncommon but are becoming more frequent (e.g. publication of full trial protocols and statistical analysis plans). Ongoing challenges hinder a large-scale implementation of some promising practices such as Registered Reports. Innovative ideas are necessary to advance peer-review efficiency and rigor in clinical trials but also to lower the cumulative burden for peer-reviewers. We make several suggestions to enhance pre-conduct peer-review. Making all steps of research process public and open may reverse siloed environments. Pre-conduct peer-review may be improved by making routinely publicly available all protocols that have gone through review by institutional review boards and regulatory agencies.

Statistical Analysis Plan (SAP) for AyuRvedic TrEatment in the Rehabilitation of Ischemic STrOke Patients in India: A Randomized Controlled Trial (RESTORE)

Background Stroke often results in a loss of functional ability. The evaluation of recovery after a stroke is crucial for both treatment and research. The AyuRvedic TrEatment in the Rehabilitation of Ischemic STrOke Patients in India: A randomized controlled trial (RESTORE) aims to generate evidence-based data for creating a uniform rehabilitation protocol and initiating a cross-referral practice to support an integrative treatment approach. The objective is to develop a detailed statistical analysis plan for the RESTORE trial prior to data analysis. Methods The statistical analysis plan was developed by the trial statistician with the assistance of the RESTORE trial principal investigator and the trial management team. The statistical analysis plan was built using the specified primary and secondary outcome measures, as well as knowledge of important baseline data. All data collected will be thoroughly examined. Results The final statistical analysis plan corresponds to established criteria and will allow for transparent and efficient reporting. Conclusions The RESTORE trial statistical analysis plan is created to reduce analysis bias caused by prior knowledge of results and to explicitly outline prespecified analysis.

Real-world response endpoints in patients with mNSCLC treated with chemotherapy across real-world datasets.

6595 Background: Response Evaluation Criteria in Solid Tumors (RECIST) based response rate (RR) is used for efficacy evaluation in clinical trials and relies on imaging data collected at specified timepoints for uniform assessment. In routine clinical practice, the method and timing of response assessment can vary, and imaging data from electronic health records (EHR) and other real world (rw) sources may not be available, making RECIST-based assessment of rw-response rate (rwRR) using rw data (RWD) challenging. Friends of Cancer Research formed a multi-stakeholder partnership to assess available data attributes to measure response across RWD sources to inform development of a consistent method for measurement. Methods: The study included seven EHR data partners who identified and analyzed a cohort of 1,380 patients (pts) with metastatic non-small cell lung cancer (mNSCLC) treated with first-line platinum doublet chemotherapy, following a common protocol and statistical analysis plan. The availability and frequency of data components to assess response including raw images, radiology imaging reports, and clinician response assessments from provider notes were assessed. Response endpoints measured included rwRR, rw-duration of response (rwDOR), and the association of rwR with rw-overall survival (rwOS), rw-time to treatment discontinuation (rwTTD), and rw-time to next treatment (rwTTNT). Results: The availability of data components varied across RWD sources (Table). Images were not widely accessible, thus response was analyzed using clinician response assessments (median proportion of pts evaluable, 77.5%). Of these assessments, the majority relied on imaging interpretation. The median rwRR was 46% with a median rwDOR of 119 days. The table provides median rwTTD, rwTTNT, and rwOS across data sources. Conclusions: The rwRR among pts with mNSCLC calculated using the clinician assessment was relatively consistent across all RWD sources, with consistent trends in time to event endpoints. While variability in the availability of data components to assess response was observed, the demonstrated feasibility of response endpoints based on clinician assessment suggests further exploration may inform drug effectiveness evaluation with RWD. [Table: see text]

Individualised versus standard duration of antibiotic therapy in children with acute uncomplicated febrile urinary tract infection: a study protocol and statistical analysis plan for a multicentre randomised clinical trial

IntroductionFebrile urinary tract infection is one of the most common bacterial infections in children. Currently, recommended antibiotic duration is 10 days. However, recent evidence suggests that 90%–95% of children with...

Evaluation of immunotherapy response score (IRS) for predicting pembrolizumab (pembro) clinical benefit in patients (pts) with advanced solid tumors.

e14646 Background: IRS is a multivariable biomarker algorithm combining tissue-based tumor mutation burden (TMB) with quantitative gene expression biomarkers, previously validated to predict anti-PD-1 and anti-PD-L1 monotherapy (mono) benefit in an observational clinical trial (PMID: 36750617). Herein, we evaluated IRS in pts with advanced solid tumors across the Kaiser Permanente Northern California (KPNC) health system following a pre-specified statistical analysis plan. Methods: KPNC pts with valid IRS results (from 2018 – 2022; specimen collection years 2011-2021) and electronic health record (EHR) documented &gt; 1st line systemic pembro mono treatment were included; pts with gliomas or previous immunotherapy were excluded. All oncologic treatments were obtained from the EHR and standardized to determine time to next treatment (TTNT) as a real-world progression free survival endpoint. A within-pt evaluation was performed, comparing pembro TTNT to the pt’s immediate prior therapy line (prior) TTNT. The primary objective was to determine if IRS status (-H vs. Low [-L]) predicts pembro clinical benefit in Cox proportional hazards models through testing for interaction between IRS status and pembro/prior therapy TTNT. Results: With a data cutoff of 06/15/2022, 211 KPNC pts (142 2nd line and 69 &gt; 2nd line pembro) were eligible and included (from 24 solid tumor types). The median (m) pembro follow-up was 16.0 months. IRS-H pts (n = 77, 36%) had significantly longer pembro vs. prior TTNT (mTTNT 20.3 mo vs. 4.5 mo, log-rank p-value &lt; 0.0001), whereas IRS-L pts (n = 134, 64%) did not (mTTNT 3.3 mo vs. 5.2 mo, log-rank p-value 0.75); the interaction between IRS status and pembro/prior treatment was significant (interaction test p-value &lt; 0.0001). Conclusions: IRS predicted pan-solid tumor pembro mono benefit compared to prior therapy and may be a potential marker for pembro mono treatment decisions. Clinical trial information: NCT03061305 .

Safety and efficacy of hydroxychloroquine as prophylactic against COVID-19 in healthcare workers: a meta-analysis of randomised clinical trials

ObjectiveWe studied the safety and efficacy of hydroxychloroquine (HCQ) as pre-exposure prophylaxis for COVID-19 in healthcare workers (HCWs), using a meta-analysis of randomised controlled trials (RCTs).Data sourcesPubMed and EMBASE databases...

Transnasal Humidified Rapid Insufflation Ventilatory Exchange in children requiring emergent intubation (Kids THRIVE): a statistical analysis plan for a randomised controlled trial

The placement of an endotracheal tube for children with acute or critical illness is a low-frequency and high-risk procedure, associated with high rates of first-attempt failure and adverse events, including hypoxaemia. To reduce the frequency of these adverse events, the provision of oxygen to the patient during the apnoeic phase of intubation has been proposed as a method to prolong the time available for the operator to insert the endotracheal tube, prior to the onset of hypoxaemia. However, there are limited data from randomised controlled trials to validate the efficacy of this technique in children. The technique known as transnasal humidified rapid insufflation ventilatory exchange (THRIVE) uses high oxygen flow rates (approximately 2 L/kg/min) delivered through nasal cannulae during apnoea. It has been shown to at least double the amount of time available for safe intubation in healthy children undergoing elective surgery. The technique and its application in real time have not previously been studied in acutely ill or injured children presenting to the emergency department or admitted to an intensive care unit. The Kids THRIVE trial is a multicentre, international, randomised controlled trial (RCT) in children less than 16 years old undergoing emergent intubation in either the intensive care unit or emergency department of participating hospitals. Participants will be randomised to receive either the THRIVE intervention or standard care (no apnoeic oxygenation) during their intubation. The primary objective of the trial is to determine if the use of THRIVE reduces the frequency of oxygen desaturation and increases the frequency of first-attempt success without hypoxaemia in emergent intubation of children compared with standard practice. The secondary objectives of the study are to assess the impact of the use of THRIVE on the rate of adverse events, length of mechanical ventilation and length of stay in intensive care. In this paper, we describe the detailed statistical analysis plan as an update of the previously published protocol.

Biomarker-guided duration of antibiotic treatment in children hospitalised with confirmed or suspected bacterial infection: statistical analysis plan for the BATCH trial and PRECISE sub-study

IntroductionThe BATCH trial is a multi-centre randomised controlled trial to compare procalcitonin-guided management of severe bacterial infection in children with current management. PRECISE is a mechanistic sub-study embedded into the BATCH trial. This paper describes the statistical analysis plan for the BATCH trial and PRECISE sub-study.MethodsThe BATCH trial will assess the effectiveness of an additional procalcitonin test in children (aged 72 h to 18 years) hospitalised with suspected or confirmed bacterial infection to guide antimicrobial prescribing decisions. Participants will be enrolled in the trial from randomisation until day 28 follow-up. The co-primary outcomes are duration of intravenous antibiotic use and a composite safety outcome. Target sample size is 1942 patients, based on detecting a 1-day reduction in intravenous antibiotic use (90% power, two-sided) and on a non-inferiority margin of 5% risk difference in the composite safety outcome (90% power, one-sided), while allowing for up to 10% loss to follow-up.ResultsBaseline characteristics will be summarised overall, by trial arm, and by whether patients were recruited before or after the pause in recruitment due to the COVID-19 pandemic. In the primary analysis, duration of intravenous antibiotic use will be tested for superiority using Cox regression, and the composite safety outcome will be tested for non-inferiority using logistic regression. The intervention will be judged successful if it reduces the duration of intravenous antibiotic use without compromising safety. Secondary analyses will include sensitivity analyses, pre-specified subgroup analyses, and analysis of secondary outcomes. Two sub-studies, including PRECISE, involve additional pre-specified subgroup analyses. All analyses will be adjusted for the balancing factors used in the randomisation, namely centre and patient age.ConclusionWe describe the statistical analysis plan for the BATCH trial and PRECISE sub-study, including definitions of clinical outcomes, reporting guidelines, statistical principles, and analysis methods. The trial uses a design with co-primary superiority and non-inferiority endpoints. The analysis plan has been written prior to the completion of follow-up.Trial registrationBATCH: ISRCTN11369832, registered 20 September 2017, doi.org/10.1186/ISRCTN11369832.PRECISE: ISRCTN14945050, registered 17 December 2020, doi.org/10.1186/ISRCTN14945050.

Albumin administration in septic shock-Protocol for post-hoc analyses of data from a multicentre RCT.

Intravenous (IV) albumin is suggested for patients with septic shock who have received large amounts of IV crystalloids; a conditional recommendation based on moderate certainty of evidence. Clinical variation in the administration of IV albumin in septic shock may exist according to patient characteristics and location. This is a protocol and statistical analysis plan for a post-hoc secondary study of the Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) RCT of 1554 adult ICU patients with septic shock. We will assess if specific baseline characteristics or trial site are associated with the administration of IV albumin during ICU stay using Cox models with competing events. All models will be adjusted for the treatment allocation in CLASSIC (restrictive vs. standard IV fluid), and all analyses will consider competing events (death, ICU discharge and loss-to-follow-up). We will present results as hazard ratios with 95% confidence intervals and p-values for the associations of baseline characteristics or site with IV albumin administration. Between-group differences (interactions) will be assessed using p-values from likelihood ratio tests. All results will be considered exploratory only. This secondary study of the CLASSIC RCT may yield important insight into potential practice variation in the administration of albumin in septic shock.

Creating a Statistical Analysis Plan to Continually Evaluate Intervention Adaptations that Arise in Real-World Implementation.

Evidence-based health interventions are frequently translated into real-world settings where practical needs drive changes to intervention protocols. Due to logistical and resource constraints, these naturally arising adaptations are rarely assessed for comparative effectiveness using a randomized trial. Nevertheless, when observational data are available, it is still possible to identify beneficial adaptations using statistical methods that adjust for differences among intervention groups. As implementation continues and more data are collected and assessed, we also require analysis methods that ensure low statistical error rates as multiple comparisons are made over time. This paper describes how to create a statistical analysis plan for evaluating adaptations to an intervention during ongoing implementation. This can be done by combining methods commonly used in platform clinical trials with methods used for real-world data. We also demonstrate how to use simulations based on previous data to decide the frequency with which to conduct statistical analyses. The illustration uses data from large-scale implementation of a school-based resilience and skill-building preventive intervention to which several adaptations were made. The proposed statistical analysis plan for evaluating the school-based intervention has potential to improve population-level outcomes as implementation scales up further and additional adaptations are anticipated.

Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with sepsis in the intensive care unit (Mega-ROX Sepsis)

BackgroundThe effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis receiving unplanned invasive mechanical ventilation in the intensive care unit (ICU) is uncertain. ObjectiveThe objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Sepsis trial. Design, setting, and participantsThe Mega-ROX Sepsis trial is an international randomised clinical trial that will be conducted within an overarching 40,000-patient registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We anticipate that between 10,000 and 13,000 patients with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU will be enrolled in this trial. Main outcome measuresThe primary outcome is in-hospital all-cause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of patients discharged home. Results and conclusionsMega-ROX Sepsis will compare the effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU. The protocol and a prespecified approach to analyses are reported here to mitigate analysis bias.

Statistical analysis plans for two randomised controlled trials of the Narrative Experiences Online (NEON) Intervention: impact of receiving recorded mental health recovery narratives on quality of life in people experiencing psychosis (NEON) and people experiencing non-psychosis mental health problems (NEON-O)

BackgroundMental health recovery narratives are a first-hand account of an individual’s recovery from mental health distress, access to narratives can aid recovery. The NEON Intervention is a web-application providing access to a managed collection of narratives. We present the statistical analysis plan for assessing the effectiveness of the NEON Intervention in improving quality of life at 1-year post-randomisation. We pay particular focus on the statistical challenges encountered due to the online nature of this trial.Methods and designThe NEON Intervention is assessed in two trial populations, one for people with experience of psychosis in the last 5 years, and mental health distress in the last six months (NEON Trial) and one for people with experience of non-psychosis mental health problems (NEON-O Trial). Both NEON trials are two-arm randomised controlled superiority trials comparing the effectiveness of the NEON Intervention with usual care. The target sample size is 684 randomised participants for NEON and 994 for NEON-O. Participants were randomised centrally in a 1:1 ratio.ResultsThe primary outcome is the mean score of subjective items on the Manchester Short Assessment of Quality-of-Life questionnaire (MANSA) at 52 weeks. Secondary outcomes are scores from the Herth Hope Index, Mental Health Confidence Scale, Meaning of Life questionnaire, CORE-10 questionnaire and Euroqol 5-Dimension 5-Level (EQ-5D-5L).ConclusionThis manuscript is the statistical analysis plan (SAP) for the NEON trials. Any post hoc analysis, such as those requested by journal reviewers will be clearly labelled as such in the final trial reporting.Trial registrationBoth trials were prospectively registered. NEON Trial: ISRCTN11152837, registered on 13 August 2018. NEON-O Trial: ISRCTN63197153, registered on 9 January 2020.

Covariates of success in quitting smoking: a systematic review of studies from 2008 to 2021 conducted to inform the statistical analyses of quitting outcomes of a hospital-based tobacco dependence treatment service in the United Kingdom

Background Smoking cessation interventions are being introduced into routine secondary care in the United Kingdom (UK), but there are person and setting-related factors that could moderate their success in quitting smoking. This review was conducted as part of an evaluation of the QUIT hospital-based tobacco dependence treatment service (https://sybics-quit.co.uk). The aim of the review was to identify a comprehensive set of variables associated with quitting success among tobacco smokers contacting secondary healthcare services in the UK who are offered support to quit smoking and subsequently set a quit date. The results would then be used to inform the development of a statistical analysis plan to investigate quitting outcomes. Methods Systematic literature review of five electronic databases. Studies eligible for inclusion investigated quitting success in one of three contexts: (a) the general population in the UK; (b) people with a mental health condition; (c) quit attempts initiated within a secondary care setting. The outcome measures were parameters from statistical analysis showing the effects of covariates on quitting success with a statistically significant (i.e., p-value &lt;0.05) association. Results The review identified 29 relevant studies and 14 covariates of quitting success, which we grouped into four categories: demographics (age; sex; ethnicity; socio-economic characteristics; relationship status, cohabitation and social network), individual health status and healthcare setting (physical health, mental health), tobacco smoking variables (current tobacco consumption, smoking history, nicotine dependence; motivation to quit; quitting history), and intervention characteristics (reduction in amount smoked prior to quitting, the nature of behavioural support, tobacco dependence treatment duration, pharmacological aids). Conclusions In total, 14 data fields were identified that should be considered for inclusion in datasets and statistical analysis plans for evaluating the quitting outcomes of smoking cessation interventions initiated in secondary care contexts in the UK. PROSPERO registration CRD42021254551 (13/05/2021)

Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: Statistical analysis plan for the WOMAN-2 trial: an international, randomised, placebo-controlled trial

Background: Postpartum haemorrhage (PPH) is responsible for over 50,000 maternal deaths every year. Most of these deaths are in low- and middle-income countries. Tranexamic acid (TXA) reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. TXA decreases surgical bleeding and reduces deaths from bleeding after traumatic injury. When given within three hours of birth, TXA reduces deaths from bleeding in women with PPH. However, for many women, treatment of PPH is too late to prevent death. World-wide, over one-third of pregnant women are anaemic and many are severely anaemic. These women have an increased risk of PPH and are more likely to die if PPH occurs. There is an urgent need to identify ways to prevent severe postpartum bleeding in anaemic women. The WOMAN-2 trial will quantify the effects of TXA on postpartum bleeding in women with anaemia. Results: This statistical analysis plan (version 1.0; dated 22 February 2023) has been written based on information in the WOMAN-2 Trial protocol version 2.0, dated 30 June 2022. The primary outcome of the WOMAN-2 trial is the proportion of women with a clinical diagnosis of primary PPH. Secondary outcomes are maternal blood loss and its consequences (estimated blood loss, haemoglobin, haemodynamic instability, blood transfusion, signs of shock, use of interventions to control bleeding); maternal health and wellbeing (fatigue, headache, dizziness, palpitations, breathlessness, exercise tolerance, ability to care for her baby, health related quality of life, breastfeeding); and other health outcomes (deaths, vascular occlusive events, organ dysfunction, sepsis, side effects, time spent in higher level facility, length of hospital stay, and status of the baby). Conclusions: WOMAN-2 will provide reliable evidence about the effects of TXA in women with anaemia. Registration: WOMAN-2 was prospectively registered at the International Standard Randomised Controlled Trials registry (ISRCTN62396133) on 07/12/2017 and ClinicalTrials.gov on 23/03/2018 (NCT03475342).

Statistical analysis plan for HOMESIDE: a randomised controlled trial for home-based family caregiver-delivered music and reading interventions for people living with dementia

BackgroundMost people with dementia live in the community, not in residential care. Therefore, quality informal care for them is critical for managing behavioural and psychological symptoms of dementia (BPSD). Music therapy has been shown to reduce BPSD. However, no randomised controlled trial has examined the effects of music interventions delivered by caregivers in home settings. The HOME-based caregiver-delivered music intervention for people living with dementia (HOMESIDE) trial aims to evaluate the effectiveness of a 12-week music intervention in addition to standard care for BPSD. This article describes the statistical analysis plan.Methods and analysisHOMESIDE is a large, pragmatic international three-arm parallel-group randomised controlled trial. Dyads (persons with dementia and caregiver) in Australia, Germany, the UK, Poland and Norway were randomised to receive music and standard care, reading and standard care or standard care alone. The primary outcome is BPSD (proxy) of the person living with dementia, measured using the Neuropsychiatric Inventory-Questionnaire (NPI-Q) at 90 and 180 days post-randomisation. Longitudinal analysis will compare NPI-Q severity between music and standard care versus standard care alone. Secondary outcomes include quality of life and depression (both person with dementia and caregiver), cognition (person with dementia only), distress, resilience, competence and caregiver-patient relationship (caregiver only). Treatment effects will be obtained at 90 and 180 days post-randomisation, where applicable. Safety outcomes (adverse events, hospitalisations, deaths) will be summarised.DiscussionThis statistical analysis plan provides a detailed methodology for the analysis of HOMESIDE and will improve the validity of the study and reduce the potential for bias.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12618001799246. Registered on November 05, 2018. ClinicalTrials.gov NCT03907748. Registered on April 09, 2019.